1. Field of the Invention
The present invention relates to certain meso-substituted tripyrrane compounds, compositions containing them, their preparation, and their use as key intermediates in synthesizing 5,10-disubstituted porphyrin compounds or other 5,10-disubstituted polypyrrolic macrocycles. In particular, the invention relates to the use of a one-step synthesis of meso-substituted tripyrranes, which offers considerable advantages with respect to the large scale, industrial production of meso-substituted porphyrins and other polypyrrolic macrocycles. Many of the meso-substituted porphyrins and polypyrrolic macrocycles made in this way are useful as:
photosensitizers for photodynamic therapy; PA1 chelators for radionuclides; PA1 MRI contrast agents (i.e., chelators for paramagnetic metals); PA1 other biomedical uses; and PA1 technical uses for infrared absorbing dyes, such as imaging, data recording and printing. PA1 all R groups are identical hydrogen, alkyl, alcohol, or carbonyl-containing groups. PA1 (a) from 5 to 100 mole % by weight of a compound of Formula I; and PA1 (b) from 0 to 95 mole % by weight of the dipyrromethane corresponding to the compound of Formula I. PA1 (a) reacting a compound of the formula: EQU Q--CHO or Q--CH(OS)(OS') PA1 S and S' are independently lower alkyl, an aryl group containing from 5 to 14 ring atoms, and --(CH.sub.2).sub.n -- where n=2-4; PA1 (c) treating the residue to remove high molecular weight polymeric materials and the corresponding dipyrromethane by-product, leaving the compound of Formula I. PA1 (a) cyclizing, in the presence of an acid catalyst, a compound of Formula I having two terminal pyrrole rings, each with an unsubstituted .alpha.-position: ##STR5## wherein: Q represents identical alkyl groups, cycloalkyl groups having from 5 to 7 ring atoms, or aryl or heteroaryl groups having from 5 to 12 ring atoms and PA1 R represents identical hydrogen, alkyl, alcohol or carbonyl-containing groups; PA1 R.sup.1 -R.sup.5 are independently hydrogen, lower alkyl, alcohol or carbonyl-containing groups; PA1 X and X' are groups capable of coupling with the unsubstituted .alpha.-positions of the terminal pyrrole rings of the compound of Formula I; PA1 Z and Z' are independently --N--, &gt;NH, --O-- or a bivalent sulfur atom; and PA1 Y is a direct link, alkylene, pyrrolylene, furanylene, phenylene, thiophenylene, benzylene, or alkylene-pyrrolene-alkylene, to form a cyclized intermediate; and PA1 (b) oxidizing the cyclized intermediate to form the corresponding 5,10-disubstituted porphyrin compound or other 5,10-disubstituted polypyrrolic macrocycle. PA1 (a) cyclizing, in the presence of an acid catalyst, a compound of Formula II: ##STR7## wherein: Q represents identical alkyl groups, cycloalkyl groups having from 5 to 7 ring atoms, or aryl or heteroaryl groups having from 5 to 12 ring atoms and PA1 R represents identical hydrogen, alkyl, alcohol or carbonyl-containing groups; PA1 Z and Z' are each --N--, &gt;NH, --O-- or --S--; PA1 Y is a direct link, alkylene, pyrrolylene, furanylene, phenylene, thiophenylene, benzylene, or alkylene-pyrrolene-alkylene; PA1 X and X' are independently hydrogen or --COOH; and PA1 G represents the atoms necessary to complete a carbocyclic or heterocyclic ring having from 5 to 14 ring atoms,
2. Description of the Related Art
.beta.-alkyl substituted tripyrrane compounds have been recognized as important building blocks for synthesizing a wide variety of polypyrrolic macrocyclic systems. For example, in 1972, Broadhurst et al. condensed a bis(pyrrolylmethyl)pyrrole diacid with a similar two-ring component, specifically, a .beta.-alkyl dipyrrin dialdehyde, to form a 22 .pi.-electron macrocycle containing five pyrrolic rings, which was named "sapphyrin." Broadhurst et al., "The Synthesis of 22 .pi.-Electron Macrocycles. Sapphyrins and Related Compounds", J.C.S. Perkin I, 2111-16 at 2112 (1972). Other workers made further contributions along the same lines, as follows:
______________________________________ Year Reported Description Source ______________________________________ 1983 Condensed a .beta.-alkyl Rexhausen et al., tripyrrane "Synthesis of a New dialdehyde with 22 .pi.-Electron a dipyrrylmethane Macrocycle: to produce a Pentaphyrin", J. pentaphyrin. Chem. Soc., Chem. Commun., 275. 1983 Coupled a Bauer et al., bipyrroledicar- "Sapphyrins: Novel boxaldehyde with a Aromatic .beta.-alkyl tripyrrane Pentapyrrolic diacid to Macrocycles", J. synthesize deca- Am. Chem. Soc., methylsapphyrin. 105, 6429-36 at 6431. 1987 Used an acid- Sessler et al., catalyzed 1:1 "Synthesis and Schiff base Crystal Structure condensation of of a Novel o-phenylenediamine Tripyrrane- or 1,4-diamino- Containing butane with a Porphyrinogen-like .beta.-alkyl diformyl- Macrocycle", J. tripyrrane to form Org. Chem., 52, a macrocycle having 4394-97 at 4395. saturated methylene bridges to link the pyrrole subunits. 1990 and Condensed an Sessler et al., 1992 .alpha.-dicarboxyalde- U.S. Pat. Nos. hyde, .beta.-alkyl 4,935,498 and tripyrrane with 5,162,509 (See o-phenylenediamine FIG. 26). to form an expanded porphyrin known as a "texaphyrin." 1992 Condensed a .beta.-alkyl Sessler et al., dicarboxylic acid "Sapphyrins and tripyrrane with a Heterosapphyrins", diformyl bipyrrole Tetrahedron, 48:44, under acidic 9661-72 at 9663. conditions in the presence of oxygen to give a deca- alkylsapphyrin. 1992 Performed an acid- Sessler et al., "A catalyzed 1:1 Nonaromatic condensation of Expanded Porphyrin 1,8-diaminoanthra- Derived from cene and a .beta.-alkyl Anthracene -- A diformyl tripyrrane Macrocycle Which to form an expanded Unexpectedly Binds porphyrin. Anions", Angew. Chem. Int. Ed. Engl., 31:4, 452-55 at 453. 1992 and Condensed 4,4'- Sessler et al., 1994 diethyl-5,5'- U.S. Pat. Nos. diformyl-3,3'- 5,302,714 (FIGS. dimethyl-2,2'- 1C and 5D) and bipyrrole and 2,5- 5,159,065. bis(5-carboxy-3- ethyl-4-methyl- pyrrol-2-ylmethyl)- 3,4-diethylpyrrole to produce 3,8,12,13,17,22- hexaethyl- 2,7,18,23- tetramethyl- sapphyrin. 1993 Reacted a .beta.-alkyl Charriere et al., tripyrrane "The Chemistry of dialdehyde with the Polyphyrins 2, corresponding .alpha.,.alpha.'- Synthesis of unsubstituted Hexaphyrins and tripyrrane to their Metal afford, after Complexes", oxidation with Heterocycles, 36:7, iodine and 1561-75 at 1562. p-benzoquinone, a .beta.-peralkyl- hexaphyrin. 1994 Condensed pyridine- Berlin et al., "New 2,6-dicarbaldehyde Porphyrinoid with a .beta.-alkyl Macrocycles tripyrranedicar- Containing boxylic acid, fol- Pyridine", Angew. lowed by oxidation Chem. Int. Ed. to form an 18-.pi. Engl., 33:2, 219-20 macrocycle called at 219. "pyriporphin." 1994 Decarboxylated a Berlin et al., .beta.-alkyl tripyrrane- "Benziporphyin, a dicarboxylic acid, Benzene-Containing condensed it with Nonaromatic isophthaladehyde, Porphyrin and oxidized the Analogue", Angew. product in situ Chem. Int. Ed. with p-chloranil to Engl., 33:12, 1246- give a benzene- 47 at 1246. containing macrocycle called "benziporphin." 1994 Performed a Schiff Sessler et al., base condensation "Texaphyrins: between a .beta.-alkyl Synthesis and diformyltripyrrane Applications", Acc. and an aromatic Chem. Res., 27, 43- 1,2-diamine, such 50 at 46. as o-phenylene- diamine derivative, to form an expanded porphyrin called a "texaphyrin." ______________________________________
However, the syntheses of the .beta.-alkyl tripyrranes used above as starting materials are generally lengthy and involve several reaction steps. Specifically, when the syntheses of .beta.-alkyl tripyrranes are described, they typically involve: (1) the reaction of an .alpha.-free, .alpha.'-ester-.beta.-tetraalkyl dipyrromethane and an .alpha.-ester, .alpha.'-carboxaldehyde-.beta.-dialkylpyrrole and subsequent reduction of the dipyrromethene moiety first formed (e.g., see Bauer et al. at 6431 and 6435) or (2) the reaction of an .alpha.-acetoxymethyl-.alpha.'-ester-.beta.-dialkylpyrrole with an .alpha.,.alpha.'-free .beta.-dialkylpyrrole, subsequent removal of the esters, and diformylation, if required (e.g., see Sessler et al., J. Org. Chem., 52 at 4395; U.S. Pat. Nos. 4,935,498, 5,162,509, 5,159,065 and 5,302,714; Sessler et al. Tetrahedron, 48:44 at 9661-63; Charriere et al., Heterocycles, 36:7 at 1567; and Seseler et al., Acc. Chem. Res., 27 at 45). The pyrrolic starting materials themselves must also be synthesized from simpler compounds, which involves several more reaction steps.
One group of workers has disclosed the reaction at room temperature of an aldehyde, such as benzaldehyde, with an excess amount of pyrrole in the absence of a solvent to produce, primarily, a meso-substituted dipyrromethane, which is used as a key building block in the synthesis of linear porphyrin arrays. Lee et al., "One-Flask Synthesis of Meso-Substituted Dipyrromethanes and Their Application in the Synthesis of Trans-Substituted Porphyrin Building Blocks", Tetrahedron, 50:39, 11427-40 (1994). Thin layer chromatography ("TLC") analysis of the reaction mixture showed, in addition to the dipyrromethane product, "a tiny amount (&lt;5%) of a tailing component." Lee et al. attempted to isolate the tailing component and "provisionally" assigned it the structure of "the corresponding tripyrromethane" based on NMR spectroscopy. However, this compound was described as being less stable than the dipyrromethane primary product and as changing "from a white solid to a black material over one day at room temperature." Lee et al. at 11429. No further efforts were made to isolate or confirm the identity of the impurity speculated to be a "tripyrromethane", and no teachings are provided by Lee et al. with respect to how to make and use the meso-substituted tripyrranes of the invention. Rather, the focus of Lee et al. is on the dipyrromethane as the desired product of the reaction, as opposed to the tripyrrane.
Rebek et al., J. Tetrahedron Lett., 35, 6823 (1994) mention briefly in the reference section of their paper a preparation for meso-phenyldipyrromethane by reacting benzaldehyde and pyrrole in the solvent toluene and in the presence of an acid catalyst, a procedure originating from a Ph.D. thesis (T. Carell, Ph.D. thesis, Ruprechts-Karl-Universitat Heidelberg (1994)). However, the production or other occurrence of any tripyrrane was not disclosed.
When others have tried to react a benzaldehyde directly with pyrrole, they have usually obtained either an inverted meso-tetraphenylporphyrin compound (specifically, 2-aza-21-carba-5,10,15,20-tetraphenylporphyrin, also known by the trivial name "N-confused porphyrin") or a mixture of the inverted tetraphenylporphyrin, non-inverted tetraphenylporphyrin, and sapphyrin. See Furuta et al., "`N-Confused Porphyrin`: A New Isomer of Tetraphenylporphyrin", J. Am. Chem. Soc., 116, 767-68 (1994); Chmielewski et al., "Tetra-p-tolylporphyrin with an Inverted Pyrrole Ring: A Novel Isomer of Porphyrin", Angew. Chem. Int. Ed. Engl., 33:7, 779-81 (1994); and Chmielewski et al., "5,10,15,20-Tetraphenylsapphyrin--Identification of a Pentapyrrolic Expanded Porphyrin in the Rothemund Synthesis", Chem. Eur. J., 1:1, 68-73 (1995). A dibenzofuranyl pyrromethane resulted when o-acetoxybenzaldehyde was heated with pyrrole in hot acetic acid. Cavaleiro et al., "An Anomalous Dipyrrole Product from Attempted Synthesis of a Tetra-arylporphyrin," J. Org. Chem., 53:5847-49 (1988). When pyrrole is reacted with 2,6-dichlorobenzaldehyde and zinc acetate, the solid phase of the reaction mixture was said to contain the desired porphyrin complex, tetrakis(2,6-dichlorophenyl)porphirato zinc(II), and the liquid phase was said to contain another product, bis(meso-2,6-dichlorophenyl)-5-(o,o'-dichlorobenzyl)dipyrromethene! zinc(II). Hill et al., "Isolation and Characterization of the Principal Kinetic Product in the Preparation of a Sterically Hindered Tetra-Arylporphyrin: X-ray Structure of a Bis(dipyrromethene) Complex of Zinc, Zn.sup.II (C.sub.22 H.sub.13 Cl.sub.4 N.sub.2).sub.2.toluene," J. Chem, Soc. Chem. Commun., 1228-29 (1985).
It has now been found that meso-substituted tripyrranes can be made in what is virtually a one-step synthesis, sometimes even without requiring the chromatographic separations usually necessary to purify polypyrrolic materials. This means that the subsequent synthesis of polypyrrolic macrocycles can be greatly simplified. Using the compounds and methods of the invention, a macrocycle such as meso-diphenylpentaphyrin, for example, can be prepared in just three steps, as compared with the 10-12 steps needed for the meso-unsubstituted, .beta.-alkylated analogue, beginning with simple pyrrolic compounds and benzaldehyde as starting materials.
Further, meso-substituted macrocycles, such as pentapyrrolic macrocycles, exhibit considerably altered spectroscopic behavior as compared with the meso-unsubstituted, .beta.-alkyl counterparts, due at least in part to the different site of substitution (.beta. only vs. meso and, optionally, also .beta.). When the meso-substituent is aryl or heteroaryl, for example, it also confers significantly different electronic properties. Further still, the addition of a large, fairly rigid and flat substituents such as aryl groups changes the steric requirements of the molecule. This alters the biological properties of meso-substituted macrocycles, as compared with their beta-alkyl analogs.
More importantly, the meso-substituents of the compounds of the invention also provide a way to manipulate the biodistribution and pharmacokinetics of the polypyrrolic macrocycles made from the compounds of the invention by changing the peripheral substitution patterns. Specifically, the most active photosensitizers used in photodynamic therapy are typically highly amphiphilic in nature. If the meso-substituents on the tripyrrane compounds of the invention are phenyl groups, for example, this presents an opportunity to introduce substituents on the phenyl groups to fine-tune the amphiphilicity, the spectroscopic properties, and/or the metal binding properties, of the resulting macrocycle even further.
To optimize the biological properties of any compound, it is of great advantage to be able to prepare whole "libraries" of related compounds. The alkyl- or aryl-substituents of the tripyrranes of the invention can be easily reacted with other monocyclic or polycyclic compounds to synthesize 5,10-disubstituted polypyrrolic macrocycles, giving access to macrocycles of an almost unlimited variety. Further, these ends are accomplished in only a few synthetic steps and, potentially, on a large scale.
Thus, the processes of the invention provide efficient methods for producing libraries of compounds having flexible, "fine-tuned" biological activity, such as precisely delivered photosensitizing ability in standard photodynamic therapy protocols.